Project Summary Parkinson?s disease (PD) is a movement disorder caused by the death of dopamine neurons in the midbrain. The disease also has non-motor symptoms (NMS), such as prominent gastrointestinal (GI) dysfunction prior to the motor deficit stage. Recent studies indicate a role for the gut-brain axis in PD pathogenesis. The microbiome has effects on gut-brain axis signaling, brain activity, and behavior. Recently, gut microbes were recognized as being required for ?-synuclein (aSyn) neuropathology, neuroinflammation, and motor deficits. PD patients have alterations in gut microbes that support the hypothesized gut-brain axis involvement. Current therapies for PD such as L-DOPA can improve motor symptoms but do not attenuate NMS or the rate of neurodegeneration. To slow or stop the underlying pathology of Parkinson?s disease in both the gut and brain, this proposal will study the therapeutic value of butyrate (short chain fatty acid) either as an oral drug or as produced by the gut microbiome in mouse models of PD and investigate treatment-associated microbiota composition shifts. I hypothesize that oral butyrate and synbiotic treatment with pre- and pro-biotics will have similar ability to reverse microbiome dysbiosis, improve GI function, and slow PD progression. Previously, our lab showed sodium phenylbutyrate (NaPB) delaying the progression of a severe form of PD called diffuse Lewy body disease (DLB) While the clinical use of NaPB therapy appears promising, a profound financial limitation exists. NaPB for human use costs about $10,000 per kg and has several side effects including allergic skin rash in about 10% of people. Results obtained from this study will indicate whether NaB can replace NaPB therapy in clinical trials, determine if synbiotic treatment can slow DLB and PD progression, (partly by increasing neuroprotection in the brain), show if synbiotic treatment can improve GI dysfunction reported by PD patients, and finally will give insight into gut-microbial shifts that may influence brain activity and GI function.